Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans. Homo sapiens

DNA methylation likely plays a role in the regulation of human stress reactivity. In a genome-wide analysis of blood DNA methylation in 85 healthy individuals a locus in the Kit ligand (KITLG) gene (cg27512205) had the strongest association with cortisol stress reactivity (p=5.8x10-6). Replication was obtained in two independent samples, one using blood (N=45, p=0.001) and the other using buccal cells (N=255,p=0.004). KITLG methylation strongly mediated the relationship between childhood trauma and cortisol stress reactivity (32% mediation). Its genomic location (CpG island shore within an H3K27ac enhancer mark) provide further evidence that KITLG methylation is functionally relevant for the programming of stress reactivity. Our results extend preclinical evidence for epigenetic regulation of stress reactivity to humans and provide leads to enhance our understanding of the neurobiological pathways underlying stress vulnerability. Overall design: Bisulphite converted DNA from whole blood of 85 healthy controls exposed to psychosocial stress task (TSST-G) was hybridised to the Illumina Infinium 450k Human Methylation Beadchip

DNA甲基化（DNA methylation）或在人类应激反应的调控中发挥关键作用。本研究对85名健康个体的血液DNA甲基化开展全基因组分析，发现Kit配体（KITLG）基因的一个位点（cg27512205）与皮质醇应激反应的关联最为显著（p=5.8×10^-6）。该关联在两个独立样本中得到重复验证：其一采用血液样本（N=45，p=0.001），其二采用口腔颊黏膜细胞样本（N=255，p=0.004）。KITLG甲基化可显著介导童年创伤与皮质醇应激反应之间的关联（介导效应占比达32%）。该位点的基因组位置（位于带有H3K27ac增强子标记的CpG岛岸（CpG island shore）区域）进一步证实，KITLG甲基化对应激反应的程序化调控具有功能相关性。本研究将应激反应表观遗传调控的临床前证据拓展至人类层面，为加深我们对应激易感性相关神经生物学通路的理解提供了研究线索。总体实验设计：对85名接受心理社会应激任务（TSST-G，特里尔社会应激测试）的健康对照者的全血亚硫酸氢盐转化DNA，采用Illumina Infinium 450k人类甲基化微珠芯片进行杂交检测。